The present invention relates generally to the field of microwave-assisted chemistry, and in particular relates to microwave-assisted hydrogenation reactions.
A number of microwave-assisted chemistry techniques are known in the academic and commercial arenas. Microwaves have some significant advantages in heating (or otherwise supplying energy to) certain substances. In particular, when microwaves interact with substances with which they can couple, most typically polar molecules or ionic species, the microwaves can immediately create a large amount of kinetic energy in such species, which can provide sufficient energy to initiate or accelerate various chemical reactions. Microwaves also have an advantage over conduction heating in that the surroundings do not need to be heated because the microwaves can react instantaneously with the desired species.
The term “microwaves” refers to that portion of the electromagnetic spectrum between about 300 and 300,000 megahertz (MHz) with wavelengths of between about one millimeter (1 mm) and one meter (1 m). These are, of course, arbitrary boundaries, but help quantify microwaves as falling below the frequencies of infrared (IR) radiation and above those referred to as radio frequencies. Similarly, given the well-established inverse relationship between frequency and wavelength, microwaves have wavelengths longer than infrared radiation, but shorter than radio frequency wavelengths.
Because of their wavelength and energy, microwaves have been historically most useful in driving robust reactions or reactions in relatively large sample amounts, or both. Stated differently, the wavelengths of most microwaves tend to create multi-mode situations in cavities in which the microwaves are being applied. In a number of types of chemical reactions, this offers little or no disadvantage, and microwave techniques are commercially well established for reactions such as digestion or loss-on-drying moisture content analysis.
Relatively robust, multi-mode microwave techniques, however, tend to be less successful when applied to small samples of materials. Although some chemistry techniques have the obvious goal of scaling up a chemical reaction, in many laboratory and research techniques, it is often necessary or advantageous to carry out chemical reactions on small samples. For example, the availability of some compounds may be limited to small samples. In other cases, the cost of reactants may discourage large sample sizes. Other techniques, such as combinatorial chemistry, use large numbers of small samples to rapidly gather a significant amount of information, and then tailor the results to provide the desired answers, such as preferred candidates for pharmaceutical compounds or their useful precursors.
Microwave devices with larger, multimode cavities that are suitable for other types of microwave-assisted techniques (e.g., drying, digestion, etc.) are generally less-suitable for smaller organic samples because the power density pattern in the cavity is relatively non-uniform.
Accordingly, the need for more focused approaches to microwave-assisted chemistry has led to improvements in devices for this purpose. For example, in the commercially available devices sold under the assignee's (CEM Corporation, 3100 Smith Farm Road, Matthews, N.C. 28106) DISCOVER®, EXPLORER®, VOYAGER®, NAVIGATOR™, LIBERTY™, and INVESTIGATOR™ trademarks have provided single mode focused microwave devices that are suitable for small samples and for sophisticated reactions such as chemical synthesis.
The very success of such single mode devices has, however, created associated problems. In particular, the improvement in power density provided by single-mode devices can cause significant heating in small samples, including undesired over-heating in some circumstances. Such over-heating can raise derivative problems when one or more of the reactants are in the gas phase. Hydrogenation represents one such reaction.
As is known to those having ordinary skill in the art, alkenes typically react in the presence of hydrogen (H2) and a catalyst to form alkanes. This reaction is known as a hydrogenation reaction. A common hydrogenation is the hardening of animal fats or vegetable oils to make them solid at room temperature and improve their stability. Hydrogen is added (in the presence of a catalyst) to carbon-carbon double bonds in the unsaturated fatty acid portion of the fat or oil molecule: Hydrogenation reactions are also important in petroleum refining; production of gasoline by cracking involves destructive hydrogenation (hydrogenolysis), in which large molecules are broken down to smaller ones and reacted with hydrogen.
Organic reactions that include a gas phase are known in the art as often lengthy and dangerous, with high potential for hydrogen gas explosions. One reason for the difficulty in conducting (e.g.) hydrogenation reactions is the necessity of working with hydrogen gas. As is known to those having ordinary skill in the art, hydrogen gas is most often stored under pressure and is a highly flammable gas. This high flammability renders hydrogen gas an undesirable reagent in lengthy reactions.
Traditional hydrogenation reactions are typically conducted at atmospheric pressure in a hydrogen atmosphere. The hydrogen atmosphere may often be provided by attaching a balloon filled with hydrogen to a round bottom flask containing the hydrogenation reactants.
Catalyst-assisted hydrogenation is also frequently carried out in a shaker-type apparatus at pressures of up to about five atmospheres and temperatures up to about 80° C. Hydrogenation instruments available from Parr Instrument Company, Moline, Ill., USA are illustrative of such techniques and represent a basic design (albeit with improvements, accessories and related enhancements) that originated in the 1920s. According to Parr, “Materials to be treated . . . are sealed in a reaction bottle with a catalyst and connected to a hydrogen reservoir. Air is removed either by evacuating the bottle or by flushing with hydrogen. Pressure is then applied from the reservoir and the bottle is shaken vigorously to initiate the reaction. The bottle can be heated or cooled during this process, if necessary. After the reaction reaches the desired point, the shaker is stopped, the bottle vented and the product and catalyst are recovered.” (www.parrinstruments.com).
Hydrogenation reactions of this sort usually have a slow reaction rate and poor reaction yields. For example, a typical hydrogenation of cholesterol takes approximately twenty four hours and evidences a yield of less than about 70%.
The lengthy reaction times, such as those described above, may subject the researcher to extended exposure to pressurized hydrogen gas, therefore creating more opportunities for problems with the hydrogen gas. Additionally, reactions with such extended reaction times are difficult to monitor continuously.
Previous attempts to utilize microwave technology for hydrogenation reactions to reduce reaction time and hydrogen gas exposure typically focused on transfer hydrogenation. “Transfer” reactions refer to hydrogenation reactions performed by producing hydrogen gas in situ rather than working with hydrogen gas maintained under pressure. A common technique for the in situ production of hydrogen gas utilizes formic acid. This technique often suffers from the drawbacks of extended reaction times and low yields.
Another technique for conducting microwave assisted hydrogenation reactions, disclosed by Heller et al in Tetrahedron Letters 46 (2005) 1247, utilizes hydrogen gas at a pressure of about 25 bar (i.e., a saturated system), a temperature of about 125° C., and a reaction time of about one hour to hydrogenate pyridine-2-carboxylic acid to give pipecoloic acid. The reaction included a minimum volume of about 20 mL and a maximum volume of about 200 mL. Similarly, hydrogenation of piperdinium utilizing the Heller method proceeded at 20 bar, 60° C., for 1.5 hours; debenzylation typically required a reaction time of about two hours, azide hydrogenation typically required a reaction time of about three hours; and hydrogenation of strychnine typically lasted about two hours.
Although this technique resulted in reduced reaction times, the necessary pressures increase the possibility of hydrogen gas explosions in the lab. Additionally, the reactions times of greater than one hour also increase the possibility of hydrogen gas explosions.